title: Attenuating effect of angiotensin-(1-7) on angiotensin II-mediated NAD(P)H oxidase activation in type 2 diabetic nephropathy of KK-A(y)/Ta mice.
abstract: ANG-(1-7) is associated with vasodilation and nitric oxide synthase stimulation. However, the role of ANG-(1-7) in type 2 diabetes mellitus is unknown. In this study, we examined the hypothesis that ANG-(1-7) attenuates ANG II-induced reactive oxygen species stress (ROS)-mediated injury in type 2 diabetic nephropathy of KK-A(y)/Ta mice. KK-A(y)/Ta mice were divided into four groups: 1) a control group; 2) ANG II infusion group; 3) ANG II+ANG-(1-7) coinfusion group; and 4) ANG II+ANG-(1-7)+d-Ala(7)-ANG-(1-7) (A779) coinfusion group. In addition, primary mesangial cells were cultured and then stimulated with 25 mM glucose with or without ANG II, ANG-(1-7), and A779. The ANG II+ANG-(1-7) coinfusion group showed a lower urinary albumin/creatinine ratio increase than the ANG II group. ANG-(1-7) attenuated ANG II-mediated NAD(P)H oxidase activation and ROS production in diabetic glomeruli and mesangial cells. ANG II-induced NF-κB and MAPK signaling activation was also attenuated by ANG-(1-7) in the mesangial cells. These findings were related to improved mesangial expansion and to fibronectin and transforming growth factor-β1 production in response to ANG II and suggest that ANG-(1-7) may attenuate ANG II-stimulated ROS-mediated injury in type 2 diabetic nephropathy. The ACE2-ANG-(1-7)-Mas receptor axis should be investigated as a novel target for treatment of type 2 diabetic nephropathy.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo, Japan.
authors.forename: Ju-Young
authors.initials: JY
authors.lastname: Moon
authors.forename: Mitsuo
authors.initials: M
authors.lastname: Tanimoto
authors.forename: Tomohito
authors.initials: T
authors.lastname: Gohda
authors.forename: Shinji
authors.initials: S
authors.lastname: Hagiwara
authors.forename: Takahiko
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Ikko
authors.initials: I
authors.lastname: Ohara
authors.forename: Maki
authors.initials: M
authors.lastname: Murakoshi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Aoki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ishikawa
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Lee
authors.forename: Kyung-Hwan
authors.initials: KH
authors.lastname: Jeong
authors.forename: Tae-Won
authors.initials: TW
authors.lastname: Lee
authors.forename: Chun-Gyoo
authors.initials: CG
authors.lastname: Ihm
authors.forename: Sung Jig
authors.initials: SJ
authors.lastname: Lim
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tomino
mesh_terms: D000803:Angiotensin I / Q000378:metabolism / Q000494:pharmacology*; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000378:metabolism*; D007150:Immunohistochemistry; D050527:Mesangial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric
chemical_list: D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D000803:Angiotensin I; D019255:NADPH Oxidases; C118790:angiotensin I (1-7)